The novel follows several characters as the "plague" is discovered as well as the panicked reaction of the public and the U.S. government to the disease.

Built into the human genome are non-coding sequences of DNA called introns. In Darwin's Radio, certain portions of these "non-sense" sequences, remnants of prehistoric retroviruses, have been activated and are translating numerous LPCs (large protein complexes). The activation of SHEVA and its consequential sudden speciation was postulated to be either controlled by a complex genetic network that perceives a need for modification or a human adaptive response to overcrowding. The disease, or rather, gene activation, is passed on laterally from male to female as per an STD. If impregnated, a woman in her first trimester who has contracted SHEVA will miscarry a deformed female fetus made of little more than two ovaries. This "first stage fetus" leaves behind a fertilized egg with fifty-two chromosomes rather than the typical forty-six characteristic of Homo sapiens sapiens.

During the third trimester of the second stage pregnancy, both parents go into a pre-speciation puberty to prepare them for the needs of their novel child. Facial pigmentation changes underneath the old skin which begins sloughing off like a mask. Vocal organs and olfactory glands alter and sensitize respectively, to adapt for a new form of communication. For over a year after the first SHEVA outbreak in the United States, no second stage fetus was recorded to have been born alive. The new human species was highly sensitive to all varieties of herpes and could not be viably born to a mother who had ever been infected with any of the virus' many forms, including Epstein-Barr and the chickenpox — thus eliminating 95% of the female population. Anesthetics and pitocin administered during childbirth were also lethal. So while many women would contract activated SHEVA, few would be able to successfully give birth, making the transition from Homo sapiens sapiens to the new human species very gradual.

The international response to the threat of SHEVA was to form a special task force that would work alongside the Centers for Disease Control and Prevention (CDC) to find a vaccine. Because the "disease", called "Herod's Flu", was already in the genome of every person on Earth, the only two options were to either inhibit the activation of the SHEVA gene by discovering the signal it used or to abort the second stage fetus. Due to the rapid mutation rate of the missing-link signal molecule, preventing the activation of the gene was infeasible. The second option, abortion, was already a controversial issue and the proposal of handing out free RU 486 was met with social upheaval, adding to the already chaotic social scene. The general public believed that the government was either not placing due importance on the death of countless fetuses, or already had a cure and refused to release it. In response, government research facilities were forced to test prospective treatments prematurely and could not pursue explanations for SHEVA outside of the "disease" category because of the potential reactions from the masses. It was not until viable second stage fetuses were born that the idea of SHEVA being a part of evolution rather than a disease began to grow from a few isolated sources.